Compound shows promise in treating melanoma

July 26, 2017 by Matt Swayne, Pennsylvania State University
Credit: Wikimedia Commons/National Cancer Institute

While past attempts to treat melanoma failed to meet expectations, an international team of researchers are hopeful that a compound they tested on both mice and on human cells in a petri dish takes a positive step toward creating a drug that can kill melanoma cancer cells without harming nearby healthy cells.

In a series of studies led by Dr. Arun Sharma, associate professor of pharmacology and Dr. Shantu Amin, professor of pharmacology, both of Penn State College of Medicine, researchers designed and synthesized a compound called napthalamide-isoselenocyanate—NISC-6—to inhibit both the Akt1 pathway and human topoisomerase IIα—topo IIα—activity, which contribute to melanoma tumor growth. Melanoma, which is caused primarily by exposure to the sun's ultraviolet rays, accounts for less than 5 percent of skin cancer cases, but causes more than 75 percent of skin cancer deaths.

In the study, the compound caused human melanoma to die and inhibited by about 69 percent in a mouse model.

According to the researchers, who report their findings in a recent issue of the European Journal of Medicinal Chemistry, recent attempts to use drugs to treat melanoma are not completely effective. Current treatments for melanoma patients include dacarbazine and temozolomide, which have an unsatisfactory response rate. Another , vemurafenib—PLX-4032—works well initially, but the tumors develop resistance within 6 to 7 months.

The researchers combined a few different approaches from their earlier work to develop the new compound.

"It was more of a fragment-based drug design," said Sharma. "We took isoselenocyanate moiety (fragments) from an earlier drug design we had worked on and then combined it with napthalamide moiety of mitonafide, a topo IIα inhibitor." Mitonafide showed antitumor activity both preclinically and in phase I and phase II clinical trials but failed due to systemic toxicity issues.

The isoselenocynate moiety was designed based on naturally occurring isothiocyanates, which can be found in vegetables, such as broccoli and cauliflower, and are known for their cancer prevention properties.

"There are a lot of recommendations that, for example, broccoli can reduce your chances of getting cancer," said Sharma. "Those are OK recommendations for prevention, but the in the vegetables alone may not be potent enough to be used in a therapeutic environment."

To improve the effectiveness, the researchers modified the drug by replacing the sulfur in a compound they studied earlier with selenium, as well as varying the length of the alkyl chain to create isoselenocynate. Several variations were screened before the researchers arrived at a compound that they thought could kill the cancer cells without increasing toxicity levels.

The researchers added that the new compound was designed to reduce toxicity and to improve drug resistance by treating melanoma cells containing wild type BRAF as well as mutated BRAF. For example, vemurafenib is more effective in melanoma containing BRAFV600E mutation, than melanoma cells with wild type BRAF protein.

"We designed it for easy elimination from the body, so, consequently, toxicity should be reduced," said Sharma. "We also think, with this compound and this type of approach, if it goes further, we should be able to delay, or overcome resistance because it not only targets BRAF mutant cells, but also BRAF wild type ."

While the researchers are still in the process of studying the actual mechanism behind how the drug works, the compound appears to target a process that guides cell division and growth, according to Deepkamal Karelia, a post-doctoral scholar in pharmacology, Penn State, who worked with Sharma.

"When a cell divides and grows, the DNA inside will become tangled much like the way a rope will if you take it and keep turning it in circles, it will get tangled. To untangle the rope you can either cut and join the rope or spend long time turning it in opposite direction to untangle it," said Karelia. "The DNA has the same issue in our cells. To solve the problem, our bodies have a protein called topoisomerase, which cuts the DNA and joins it back to release the stress. What we show in this paper is this compound may be able to inhibit that activity of topo IIα protein—the DNA is unable to unwind itself."

Sharma said NISC-6 may also work on other forms of cancer, which will likely be included in future research.

Explore further: Researchers discover mechanism leading to BRAF inhibitor resistance in melanoma

Related Stories

Researchers discover mechanism leading to BRAF inhibitor resistance in melanoma

June 19, 2015
The development of targeted therapies has significantly improved the survival of melanoma patients over the last decade; however, patients often relapse because many therapies do not kill all of the tumor cells, and the remaining ...

New insight into drug resistance in metastatic melanoma

June 3, 2014
(Medical Xpress)—A study by scientists in Manchester has shown how melanoma drugs can cause the cancer to progress once a patient has stopped responding to treatment.

Drug combination delivered by nanoparticles may help in melanoma treatment

March 15, 2017
The first of a new class of medication that delivers a combination of drugs by nanoparticle may keep melanoma from becoming resistant to treatment, according to Penn State College of Medicine researchers.

Promising new drug stops spread of melanoma by 90 percent

January 4, 2017
Michigan State University researchers have discovered that a chemical compound, and potential new drug, reduces the spread of melanoma cells by up to 90 percent.

New drug, Vemurafenib, doubles survival of metastatic melanoma patients

March 1, 2012
A report published this week in the New England Journal of Medicine shows that the 50 percent of metastatic melanoma patients with a specific genetic mutation benefit from the drug Vemurafenib – increasing median survival ...

Scientists identify promising new melanoma drug

November 25, 2015
A new drug discovered by scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) may show promise for treating skin cancers that are resistant or unresponsive to today's leading therapies.

Recommended for you

Treatment shown to improve the odds against bone marrow cancer

December 15, 2018
Hope has emerged for patients with a serious type of bone marrow cancer as new research into a therapeutic drug has revealed improved outcomes and survival rates.

Immunotherapy combo not approved for advanced kidney cancer patients on the NHS

December 14, 2018
People with a certain type of advanced kidney cancer will not be able to have a combination of two immunotherapy drugs on the NHS in England.

New drug seeks receptors in sarcoma cells, attacks tumors in animal trials

December 13, 2018
A new compound that targets a receptor within sarcoma cancer cells shrank tumors and hampered their ability to spread in mice and pigs, a study from researchers at the University of Illinois reports.

Surgery unnecessary for many prostate cancer patients

December 13, 2018
Otherwise healthy men with advanced prostate cancer may benefit greatly from surgery, but many with this diagnosis have no need for it. These conclusions were reached by researchers after following a large group of Scandinavian ...

Lethal combination: Drug cocktail turns off the juice to cancer cells

December 12, 2018
A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth—this was discovered by researchers from the University of Basel's Biozentrum two years ago. In a follow-up study, ...

Combining three treatment strategies may significantly improve melanoma treatment

December 12, 2018
A study by a team led by a Massachusetts General Hospital (MGH) investigator finds evidence that combining three advanced treatment strategies for malignant melanoma—molecular targeted therapy, immune checkpoint blockade ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.